tbuckley/cabot-search huggingface dataset:
Daily Low-Volume Paracentesis and Clinical Complications in Patients With Refractory Ascites
Authors: Tammo L. Tergast, Marie Griemsmann, Lena Stockhoff, Kerstin Port, Benjamin Heidrich, Markus Cornberg, Heiner Wedemeyer, Henrike Lenzen, Nicolas Richter, Elmar Jaeckel, Benjamin Maasoumy
Journal: JAMA Network Open (2023)

Importance The potential association of low-volume paracentesis of less than 5 L with complications in patients with ascites remains unclear, and individuals with cirrhosis and refractory ascites (RA) treated with devices like Alfapump or tunneled-intraperitoneal catheters perform daily low-volume drainage without albumin substitution. Studies indicate marked differences regarding the daily drainage volume between patients; however, it is currently unknown if this alters the clinical course. Objective To determine whether the incidence of complications, such as hyponatremia or acute kidney injury (AKI), is associated with the daily drainage volume in patients with devices. Design, Setting, and Participants This retrospective cohort study of patients with liver cirrhosis, RA, and a contraindication for a transjugular intrahepatic portosystemic shunt who received either device implantation or standard of care (SOC; ie, repeated large-volume paracentesis with albumin infusion), and were hospitalized between 2012 and 2020 were included. Data were analyzed from April to October 2022. Interventions Daily ascites volume removed. Main outcomes and Measures The primary end points were 90-day incidence of hyponatremia and AKI. Propensity score matching was performed to match and compare patients with devices and higher or lower drainage volumes to those who received SOC. Results Overall, 250 patients with RA receiving either device implantation (179 [72%] patients; 125 [70%] male; 54 [30%] female; mean [SD] age, 59 [11] years) or SOC (71 [28%] patients; 41 [67%] male; 20 [33%] female; mean [SD] age, 54 [8]) were included in this study. A cutoff of 1.5 L/d or more was identified to estimate hyponatremia and AKI in the included patients with devices. Drainage of 1.5 L/d or more was associated with hyponatremia and AKI, even after adjusting for various confounders (hazard ratio [HR], 2.17 [95% CI, 1.24-3.78]; P = .006; HR, 1.43 [95% CI, 1.01-2.16]; P = .04, respectively). Moreover, patients with taps of 1.5 L/d or more and less than 1.5 L/d were matched with patients receiving SOC. Those with taps of 1.5 L/d or more had a higher risk of hyponatremia and AKI compared with those receiving SOC (HR, 1.67 [95% CI, 1.06-2.68]; P = .02 and HR, 1.51 [95% CI, 1.04-2.18]; P = .03), while patients with drainage of less than 1.5 L/d did not show an increased rate of complications compared with those receiving SOC. Conclusions and Relevance In this cohort study, clinical complications in patients with RA performing low-volume drainage without albumin infusion were associated with the daily volume drained. Based on this analysis, physicians should be cautious in patients performing drainage of 1.5 L/d or more without albumin infusion.
GRP/GRPR enhances alcohol-associated liver injury through the IRF1-mediated Caspase-1 inflammasome and NOX2-dependent ROS pathway
Authors: Haidi Li, Xin Chen, Jiejie Xu, Lin Zhu, Chao Li, Xiaolong Sun, Xiaofeng Li, Jianbo Guo, Juanjuan Li, Sheng Wang, Yong He, Hua Wang, Cheng Huang, Xiao-ming Meng, Jun Li
Journal: Hepatology (2023)

Background and Aims: The common characteristics of alcohol-associated liver injury (ALI) include abnormal liver function, infiltration of inflammatory cells, and generation of oxidative stress. The gastrin-releasing peptide receptor (GRPR) is activated by its neuropeptide ligand, gastrin-releasing peptide (GRP). GRP/GRPR appears to induce the production of cytokines in immune cells and promotes neutrophil migration. However, the effects of GRP/GRPR in ALI are unknown. Approach and Results: We found high GRPR expression in the liver of patients with alcohol-associated steatohepatitis and increased pro-GRP levels in peripheral blood mononuclear cells of these patients compared with that of the control. Increased expression of GRP may be associated with histone H3 lysine 27 acetylation induced by alcohol, which promotes the expression of GRP and then GRPR binding. Grpr -/- and Grpr flox/flox LysM Cre mice alleviated ethanol-induced liver injury with relieved steatosis, lower serum alanine aminotransferase, aspartate aminotransferase, triglycerides, malondialdehyde, and superoxide dismutase levels, reduced neutrophil influx, and decreased expression and release of inflammatory cytokines and chemokines. Conversely, the overexpression of GRPR showed opposite effects. The pro-inflammatory and oxidative stress roles of GRPR might be dependent on IRF1-mediated Caspase-1 inflammasome and NOX2-dependent reactive oxygen species pathway, respectively. In addition, we verified the therapeutic and preventive effects of RH-1402, a novel GRPR antagonist, for ALI. Conclusions: A knockout or antagonist of GRPR during excess alcohol intake could have anti-inflammatory and antioxidative roles, as well as provide a platform for histone modification-based therapy for ALI.
The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision
Authors: Lies Langouche, Arno Téblick, Jan Gunst, Greet Van den Berghe
Journal: Endocrine Reviews (2023)

Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.
Diabetes of the Exocrine Pancreas: Implications for Pharmacological Management
Authors: Mark O. Goodarzi, Maxim S. Petrov
Journal: Drugs (2023)

Post-pancreatitis diabetes mellitus, pancreatic cancer-related diabetes, and cystic fibrosis-related diabetes are often underappreciated. As a result, a substantial proportion of people with these sub-types of diabetes receive antidiabetic medications that may be suboptimal, if not harmful, in the context of their underlying disease of the exocrine pancreas. The present article delineates both classical (biguanides, insulin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, and meglitinides) and newer (glucagon-like peptide-1 receptor agonists, amylin analogs, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors, D2 receptor agonists, bile acid sequestrants, and dual glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor co-agonists) therapies and provides recommendations for managing people with diabetes of the exocrine pancreas based on the most up-to-date clinical evidence. Also, several emerging directions (lipid-enriched pathways, Y4 receptor agonism, glucagon-like peptide-1 and glucagon receptor co-agonism) are presented with a view to informing the process of new drug discovery and development.
Nationwide, population-based observational study of the molecular epidemiology and temporal trend of carbapenemase-producing Enterobacterales in Norway, 2015 to 2021
Authors: Oskar Ljungquist, Bjørg Haldorsen, Anna Kaarina Pöntinen, Jessin Janice, Ellen Haldis Josefsen, Petter Elstrøm, Oliver Kacelnik, Arnfinn Sundsfjord, Ørjan Samuelsen
Journal: Eurosurveillance (2023)

Introduction National and regional carbapenemase-producing Enterobacterales (CPE) surveillance is essential to understand the burden of antimicrobial resistance, elucidate outbreaks, and develop infection-control or antimicrobial-treatment recommendations. Aim This study aimed to describe CPE and their epidemiology in Norway from 2015 to 2021. Methods A nationwide, population-based observational study of all verified clinical and carriage CPE isolates submitted to the national reference laboratory was conducted. Isolates were characterised by antimicrobial susceptibility testing, whole genome sequencing (WGS) and basic metadata. Annual CPE incidences were also estimated. Results A total of 389 CPE isolates were identified from 332 patients of 63 years median age (range: 0–98). These corresponded to 341 cases, 184 (54%) being male. Between 2015 and 2021, the annual incidence of CPE cases increased from 0.6 to 1.1 per 100,000 person-years. For CPE-isolates with available data on colonisation/infection, 58% (226/389) were associated with colonisation and 38% (149/389) with clinical infections. WGS revealed a predominance of OXA-48-like (51%; 198/389) and NDM (34%; 134/389) carbapenemases in a diversified population of Escherichia coli and Klebsiella pneumoniae , including high-risk clones also detected globally. Most CPE isolates were travel-related (63%; 245/389). Although local outbreaks and healthcare-associated transmission occurred, no interregional spread was detected. Nevertheless, 18% (70/389) of isolates not directly related to import points towards potentially unidentified transmission routes. A decline in travel-associated cases was observed during the COVID-19 pandemic. Conclusions The close-to-doubling of CPE case incidence between 2015 and 2021 was associated with foreign travel and genomic diversity. To limit further transmission and outbreaks, continued screening and monitoring is essential.
Psychiatric Boarding Trends Among Publicly Insured Youths During the COVID-19 Pandemic—The Other Pandemic
Authors: Abigail L. Donovan
Journal: JAMA Network Open (2023)

Psychiatric boarding is a crucial clinical and mental health systems challenge deserving attention and discussion.In the JAMA Network Open article, Herrera et al 1 studied psychiatric boarding among publicly insured youths, ages 4 to 20 years (mean age, 13.6 years), who had been evaluated by a mobile crisis team (MCT) in Massachusetts.They compared boarding rates, boarding length of stay, disposition after boarding, and re-presentation within 30 days before and during the COVID-19 pandemic.They found that during the first 18 months of the pandemic, the odds of an MCT encounter resulting in boarding for publicly insured youths doubled, while simultaneously boarding encounters were significantly less likely to end with admission to inpatient or residential care.In addition, publicly insured youths who experienced boarding had significantly more readmissions within 30 days.This report paints a stark picture of psychiatric emergency services for publicly insured youths during the pandemic.The study population of publicly insured youths represents a vulnerable group experiencing a psychiatric crisis so severe that either inpatient or residential care is initially required, 80% of whom were youths of color.While boarding, these youths were supervised, kept in a safe environment, and may have had pharmacotherapy, but no additional treatment was available.Compared with their prepandemic counterparts, a larger percentage of these youths never received the higher level of care they required; they were eventually discharged home, and a portion of them received no additional services.
Strain-level screening of human gut microbes identifies <i>Blautia producta</i> as a new anti-hyperlipidemic probiotic
Authors: Wenyi Xu, Jiaqi Yu, Yanan Yang, Zhuanyu Li, Yinghui Zhang, Fang Zhang, Qingshi Wang, Yong Xie, Bowen Zhao, Chongming Wu
Journal: Gut Microbes (2023)

Compelling evidence has tightly linked gut microbiota with host metabolism homeostasis and inspired novel therapeutic potentials against metabolic diseases (e.g., hyperlipidemia). However, the regulatory profile of individual bacterial species and strain on lipid homeostasis remains largely unknown. Herein, we performed a large-scale screening of 2250 human gut bacterial strains (186 species) for the lipid-decreasing activity. Different strains in the same species usually displayed distinct lipid-modulatory actions, showing evident strain-specificity. Among the tested strains, Blautia producta exhibited the most potency to suppress cellular lipid accumulation and effectively ameliorated hyperlipidemia in high fat diet (HFD)-feeding mice. Taking a joint comparative approach of pharmacology, genomics and metabolomics, we identified an anteiso-fatty acid, 12-methylmyristic acid (12-MMA), as the key active metabolite of Bl. Producta. In vivo experiment confirmed that 12-MMA could exert potent hyperlipidemia-ameliorating efficacy and improve glucose metabolism via activating G protein-coupled receptor 120 (GPR120). Altogether, our work reveals a previously unreported large-scale lipid-modulatory profile of gut microbes at the strain level, emphasizes the strain-specific function of gut bacteria, and provides a possibility to develop microbial therapeutics against hyperlipidemia based on Bl. producta and its metabolite.
CDK4/6-MEK Inhibition in MPNSTs Causes Plasma Cell Infiltration, Sensitization to PD-L1 Blockade, and Tumor Regression
Authors: Jordan L. Kohlmeyer, Joshua J. Lingo, Courtney A. Kaemmer, Amanda Scherer, Akshaya Warrier, Ellen Voigt, Juan A. Raygoza Garay, Gavin R. McGivney, Qierra R. Brockman, Amy Tang, Ana Calizo, Kai Pollard, Xiaochun Zhang, Angela C. Hirbe, Christine A. Pratilas, Mariah Leidinger, Patrick Breheny, Michael S. Chimenti, Jessica C. Sieren, Varun Monga, Munir R. Tanas, David K. Meyerholz, Benjamin W. Darbro, Rebecca D. Dodd, Dawn E. Quelle
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are lethal, Ras-driven sarcomas that lack effective therapies. We investigated effects of targeting cyclin-dependent kinases 4 and 6 (CDK4/6), MEK, and/or programmed death-ligand 1 (PD-L1) in preclinical MPNST models. Experimental Design: Patient-matched MPNSTs and precursor lesions were examined by FISH, RNA sequencing, IHC, and Connectivity-Map analyses. Antitumor activity of CDK4/6 and MEK inhibitors was measured in MPNST cell lines, patient-derived xenografts (PDX), and de novo mouse MPNSTs, with the latter used to determine anti–PD-L1 response. Results: Patient tumor analyses identified CDK4/6 and MEK as actionable targets for MPNST therapy. Low-dose combinations of CDK4/6 and MEK inhibitors synergistically reactivated the retinoblastoma (RB1) tumor suppressor, induced cell death, and decreased clonogenic survival of MPNST cells. In immune-deficient mice, dual CDK4/6-MEK inhibition slowed tumor growth in 4 of 5 MPNST PDXs. In immunocompetent mice, combination therapy of de novo MPNSTs caused tumor regression, delayed resistant tumor outgrowth, and improved survival relative to monotherapies. Drug-sensitive tumors that regressed contained plasma cells and increased cytotoxic T cells, whereas drug-resistant tumors adopted an immunosuppressive microenvironment with elevated MHC II-low macrophages and increased tumor cell PD-L1 expression. Excitingly, CDK4/6-MEK inhibition sensitized MPNSTs to anti–PD-L1 immune checkpoint blockade (ICB) with some mice showing complete tumor regression. Conclusions: CDK4/6-MEK inhibition induces a novel plasma cell-associated immune response and extended antitumor activity in MPNSTs, which dramatically enhances anti–PD-L1 therapy. These preclinical findings provide strong rationale for clinical translation of CDK4/6-MEK-ICB targeted therapies in MPNST as they may yield sustained antitumor responses and improved patient outcomes.
Naloxone Accessibility Under the State Standing Order Across Mississippi
Authors: Emily Gravlee, Sujith Ramachandran, Anne Cafer, Erin Holmes, Jacob McGregor, Taylor Jordan, Meagen Rosenthal
Journal: JAMA Network Open (2023)

Importance Naloxone is a life-saving medication for individuals experiencing an opioid overdose. Naloxone standing orders aim to make naloxone more available by allowing patients improved access to this medication at community pharmacies; however, lawful availability does not mean that this life-saving intervention is accessible to patients. Objective To characterize naloxone availability and out-of-pocket cost under the state standing order in Mississippi. Design, Setting, and Participants This telephone-based, mystery-shopper census survey study included Mississippi community pharmacies open to the general public in Mississippi at the time of data collection. Community pharmacies were identified using the Hayes Directories April 2022 complete Mississippi pharmacy database. Data were collected from February to August 2022. Exposures Mississippi House bill 996, the Naloxone Standing Order Act, signed into law in 2017, allowing pharmacists to dispense naloxone under a physician state standing order at a patient’s request. Main Outcomes and Measures The main outcomes were naloxone availability under Mississippi’s state standing order and the out-of-pocket cost of available formulations. Results There were 591 open-door community pharmacies surveyed for this study, with a 100% response rate. The most common pharmacy type was independent (328 [55.50%]), followed by chain (147 [24.87%]) and grocery store (116 [19.63%]). When asked, “Do you have naloxone that I can pick up today?” 216 Mississippi pharmacies (36.55%) had naloxone available for purchase under the state standing order. Of the 591 pharmacies, 242 (40.95%) were unwilling to dispense naloxone under the state standing order. Among the 216 pharmacies with naloxone available, the median out-of-pocket cost for naloxone nasal spray (n = 202) across Mississippi was $100.00 (range, $38.11-$229.39; mean [SD], $105.58 [$35.42]) and the median out-of-pocket cost of naloxone injection (n = 14) was $37.70 (range, $17.00-$208.96; mean [SD], $66.62 [$69.27]). Conclusions and Relevance In this survey study of open-door Mississippi community pharmacies, availability of naloxone was limited despite standing order implementation. This finding has important implications for the effectiveness of the legislation in preventing opioid overdose deaths in this region. Further studies are needed to understand pharmacists’ unwillingness to dispense naloxone and the implications of lack of availability and unwillingness for further naloxone access interventions.
Thigh pain after total hip arthroplasty
Authors: Xiao-Qiang Wang, Xiao-Qiang Ren, De-An Qin
Journal: International Journal of Surgery (2023)

aDepartment of Medical imaging center, Shanxi Provincial People's Hospital bDepartment of Medical information center, Shanxi Provincial People's Hospital cDepartment of Orthopedics, Shanxi Provincial People's Hospital, Taiyuan 030012, Shanxi, China No additional unpublished data are available Thigh pain after total hip arthroplasty Published online ■ ■ *Corresponding author. Address: Department of Orthopedics, Shanxi Provincial People's Hospital, NO. 29, Double Tower Street, Taiyuan 030012, Shanxi, China. Tel: +8615034428643. E-mail: [email protected] (D.-A. Qin). This is an open access article distributed under the Creative Commons Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. http://creativecommons.org/licenses/by-sa/4.0/
Local Salmonella Enteritidis restaurant outbreak investigation in England provides further evidence for eggs as source in widespread international cluster, March to April 2023
Authors: Helen E Benson, Lucy Reeve, Lucy Findlater, Amoolya Vusirikala, Maaike Pietzsch, Oluwakemi Olufon, Eve Matthews, Ann Hoban, Anaïs Painset, Sooria Balasegaram, Lesley Larkin, Sarah Weir, Ellen Heinsbroek
Journal: Eurosurveillance (2023)

We report a 5-single nucleotide polymorphism cluster of Salmonella Enteriditis in England, part of a global cluster of S. Enteritidis ST11. Forty-seven confirmed cases have been investigated of whom 25 were linked to a restaurant. In addition, there were 18 probable cases with restaurant exposure. Epidemiological investigations suggested eggs or chicken as the most likely cause of the outbreak but were unable to distinguish between those two food vehicles. Ongoing food chain investigations indicated links to imported eggs from Poland.
Lung cancer risk score for ever and never smokers in China
Authors: Zhimin Ma, Jun Lv, Meng Zhu, Canqing Yu, Hongxia Ma, Guangfu Jin, Yu Guo, Zheng Bian, Ling Yang, Yiping Chen, Zhengming Chen, Zhibin Hu, Liming Li, Hongbing Shen
Journal: Cancer Communications (2023)

Abstract Background Most lung cancer risk prediction models were developed in European and North‐American cohorts of smokers aged ≥ 55 years, while less is known about risk profiles in Asia, especially for never smokers or individuals aged &lt; 50 years. Hence, we aimed to develop and validate a lung cancer risk estimate tool for ever and never smokers across a wide age range. Methods Based on the China Kadoorie Biobank cohort, we first systematically selected the predictors and explored the nonlinear association of predictors with lung cancer risk using restricted cubic splines. Then, we separately developed risk prediction models to construct a lung cancer risk score (LCRS) in 159,715 ever smokers and 336,526 never smokers. The LCRS was further validated in an independent cohort over a median follow‐up of 13.6 years, consisting of 14,153 never smokers and 5,890 ever smokers. Results A total of 13 and 9 routinely available predictors were identified for ever and never smokers, respectively. Of these predictors, cigarettes per day and quit years showed nonlinear associations with lung cancer risk ( P non‐linear &lt; 0.001). The curve of lung cancer incidence increased rapidly above 20 cigarettes per day and then was relatively flat until approximately 30 cigarettes per day. We also observed that lung cancer risk declined sharply within the first 5 years of quitting, and then continued to decrease but at a slower rate in the subsequent years. The 6‐year area under the receiver operating curve for the ever and never smokers’ models were respectively 0.778 and 0.733 in the derivation cohort, and 0.774 and 0.759 in the validation cohort. In the validation cohort, the 10‐year cumulative incidence of lung cancer was 0.39% and 2.57% for ever smokers with low (&lt; 166.2) and intermediate‐high LCRS (≥ 166.2), respectively. Never smokers with a high LCRS (≥ 21.2) had a higher 10‐year cumulative incidence rate than those with a low LCRS (&lt; 21.2; 1.05% vs . 0.22%). An online risk evaluation tool (LCKEY; http://ccra.njmu.edu.cn/lckey/web ) was developed to facilitate the use of LCRS. Conclusions The LCRS can be an effective risk assessment tool designed for ever and never smokers aged 30 to 80 years.